Project 2 addresses the later events in skin cancer development leading to malignant conversion and an approach to therapy. We show that molecular profiling produces a signature of gene expression that distinguishes between benign tumors at low and high risk for premalignant progression. This gene list allowed us to determine the progression risk for a group of unknown samples. We also determined that CLIC4 can serve as a marker for progression of a variety of human and experimental cancers. As cancers progress, CLIC4 is lost from the cancer cells and induced in stromal cells. The stromal change is associated with fibroblast to myofibroblast conversion and is convergent with the induction of alpha smooth muscle actin. Overexpression of exogenous CLIC4 in tumor cells in vivo inhibits tumor growth while overexpression of exogenous CLIC4 in stromal cells enhances tumor growth. Mechanistic studies suggest that nuclear CLIC4 participates in the TGF beta pathway through interactions with Schnurri 2 and Smads. Finally, we report that a protein kinase C activator in clinical trials for the treatment of skin cancer induces a hemorrhagic necrosis through interactions with immunophilins.